Oncology
Paragangliomas and pheochromocytomas (PPGLs) are rare endocrine tumors and highly enriched for germline mutations. The Endocrine Society guidelines published in 2014 recommend succinate dehydrogenase (SDH) gene testing for patients with paragangliomas, with SDHB testing specifically recommended for those with metastatic disease. In addition, sequential genetic testing is recommended based on a decisional algorithm with priority given to syndromic or metastatic presentation, as well as additional consideration for age of diagnosis and family history. We sought to determine the proportion of individuals with mutations identified through concurrent multi-gene testing that may not be captured under current recommendations.
Test request forms and clinic notes were retrospectively reviewed for 671 individuals undergoing germline genetic testing for PPGL or related tumors via a 12 gene panel (FH, MAX, MEN1, NF1, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, VHL) between August 2014 through September 2015.
Of individuals tested, 174 (25.9%) had positive results, 419 (62.4%) had negative results, and 88 (13.1%) had at least one variant of uncertain significance (VUS). The SDH genes were most frequently positive (SDHB, 48.3%; SDHD, 19.0%; SDHA, 10.3%; SDHC, 6.9%), with mutations in other genes each accounting for the remainder (VHL, 5.2%; RET and TMEM127, 2.9% each; MAX, 2.3%; NF1 and SDHAF2, 1.1% each). No mutations were detected in FH or MEN1. Sixteen individuals had mutations in syndromic genes (NF1, RET, VHL), only 5 (31.2%) met diagnostic criteria. Tumors were reported in 157 positive patients, 146 (92.9%) were PPGLs. Individuals with a personal diagnosis of PPGL and a family history of PPGL and/or kidney cancer, separately or in combination was reported in 37/146 (25.3%).
A significant portion of positive individuals had mutations in genes outside the SDH complex (25/174, 14.4%), highlighting the strength of expanded testing in the identification of at-risk patients. Individuals that may be underappreciated in current guidelines include those with non-PPGL tumors (11/157, 7.0%), those not meeting criteria for syndromic conditions (11/16, 68.8%), and those without family history of PPGL and/or kidney cancer (109/146, 74.7%). Taken together, these considerations support the use of concurrent multi-gene panel testing for individuals with PPGLs.